Hot flashes pose a significant public health problem because they are the most common perimenopausal symptom reported by women in the United States and the primary reason that women seek medical care during the menopausal transition. Despite the importance of hot flashes in a woman's life, little is known about the risk factors for this symptom. Our preliminary data from 195 women (aged 45-54 years) suggest that phthalate exposures are associated with an increased risk of hot flashes. Specifically, higher concentrations of phthalates commonly found in personal care products (PCPs) were associated with an increased risk of ever having hot flashes, having hot flashes in the past 30 days, and frequent hot flashes. Further, our preliminary data suggest that increased levels of phthalate metabolites are associated with reduced antral follicle counts, a known risk factor for hot flashes in women. Thus, the overall goal of this application is to extend our preliminary analysis by testing the hypothesis that urinary phthalate metabolite concentrations are associated with hot flashes and explore their associations with potential mechanisms of hot flashes that involve low estrogen levels and ovarian failure. To test this hypothesis, we propose to complete the following specific aims: 1) prospectively determine whether urinary levels of phthalate metabolites are associated with subsequent hot flashes, 2) determine whether urinary levels of phthalate metabolites are associated with low estrogen and androgen levels, 3) determine whether urinary levels of phthalate metabolites are associated with ovarian follicle loss, and 4) explore whether any observed associations between urinary phthalate metabolites and hot flashes are mediated by ovarian follicle loss and/or low levels of sex steroid hormones. To complete these aims, we will use urine and blood samples, transvaginal ultrasound data, and hot flashes histories that have been obtained from 782 women (aged 45-54 years) who participated in the Midlife Women's Health Study. The urine samples will be subjected to measurements of phthalate metabolites and the blood samples will be subjected to measurements of sex steroid hormone levels as well as anti-Mllerian and inhibin B levels. Transvaginal ultrasound data will be used to determine antral follicle counts and ovarian volume. Statistical analyses then will be conducted to assess correlations between urinary phthalate levels, hormone levels, antral follicle numbers, and ovarian volume. Further, statistical analyses will be conducted to examine whether low sex steroid hormone levels, reduced antral follicle counts, or small ovarian reserve mediate the association between phthalate metabolites and hot flashes. The results of this study will provide a better understanding of the risk factors for hot flashes and the mechanisms by which environmental chemicals are associated with adverse reproductive outcomes in women. This may lead to the development of preventive strategies and new treatments for hot flashes in women.